Master of Science

thesisTraditional geothermal systems have been limited to geologic systems in which elevated temperatures, abundant water, and high porosity and permeability are found. Engineered geothermal systems (EGS) have been proposed for thermal reservoirs in which insufficient water and/or permeability are present. The EGS model calls for the creation of large fracture networks which penetrate the hot rock resource. These fracture networks are formed by reopening sealed fractures or by creating new fractures using hydraulic fracturing methods common to the oil and gas industry. Application of hydraulic fracturing technologies in geothermal systems and operation of engineered geothermal systems present new issues including the formation of thermal fractures due to temperature differentials and rock shrinkage; and the performance of hydraulic fracturing materials such as proppants under geothermal conditions. The formation of thermal fractures in a geothermal reservoir will be governed by the thermophysical properties of the reservoir rock, including heat capacity, thermal conductivity, coefficient of thermal expansion, etc. Thermal conductivity may be estimated using data obtained from geophysical well logs. Multivariate data analysis methods such as principal components analysis and regression analysis have been used to interpret log data. Significant discrepancies between experimentally-determined thermal conductivity and model-derived thermal conductivity were noted. Possible sources of the discrepancies include rock anisotropy and insufficient data. However, principal components analysis proved to be a valuable resource for data interpretation. The resilience of proppants under geothermal conditions was evaluated. Three proppant types were tested in the presence of water and crushed granite at elevated temperatures for periods up to 11 weeks. Sintered bauxite proppant was found to be susceptible to dissolution in hot geothermal water. Quartz sand proppant and resin-coated bauxite proppant appeared to experience less dissolution. Sintered bauxite and resin-coated bauxite proppants were crush tested both before and after exposure to geothermal conditions and the resistance of the proppants to crushing remained unchanged. Based on the testing regime, resin-coated bauxite proppant appears to be well-suited for use in engineered geothermal systems

Missing Data Methods for ICU SOFA Scores in Electronic Health Records Studies: Results from a Monte Carlo Simulation Study

This study utilizes electronic health record data from the Medical University of South Carolina’s intensive care units as the basis for this Monte Carlo simulation study— which compares four methods for handling missing SOFA scores, both at the composite and component levels. The four methods examined herein include: complete case analysis, median imputation, zero imputation (the method recommended by the creators of the SOFA score), and multiple imputation. This study found that zero imputation introduced the most bias across all three outcomes studied, and therefore is not recommended. Complete case analysis, or ignoring missing data, caused varying amounts of bias—as did median imputation. Multiple imputation, on the other hand, performed well for all three outcomes studied, both at the composite and component levels, demonstrating this method’s superior value in the presence of missing SOFA scores

Interfacial Microrheology of Biological Films

This thesis reports experimental studies of the rheology of biological materials, with an emphasis on interfacial layers, including protein layers and bacterial biofilms. Results are presented on layers formed by the proteins lysozyme and Staphylococcal nuclease at the air--water interface, on biofilms formed by Pseudomonas bacteria at the oil--water interface, and on the bulk rheological properties of fibrin and cystic fibrosis mucus with an eye toward its role as an interfacial barrier in the lung. The evolution of interfacial mechanical response through time is interpreted in terms of the changing microscopic structure of the layer. The studies employ interfacial microrheology, which uses the motion of micrometer-scale particles embedded in the interface to probe the mechanical response of the surrounding material and infer its rheology. Passive measurements, which rely on thermal forces to drive the particles, are complemented by active measurements, in which ferromagnetic nanowires were rotated using magnetic fields. Additionally, the study of fibrin and cystic fibrosis mucus employs a novel technique using custom fluorescent particles that can be selectively ``switched on'' and used to characterize rheology and particle mobility over physiologically relevant time and distance scales. This thesis also presents a software toolkit, developed as part of the thesis work to meet the demands of this research, that has found applications by other researchers in other areas. This work was conducted under the supervision of Professor Robert L. Leheny and Professor Daniel H. Reich

Spatial Epidemiology: Current Approaches and Future Challenges

Spatial epidemiology is the description and analysis of geographic variations in disease with respect to demographic, environmental, behavioral, socioeconomic, genetic, and infectious risk factors. We focus on small-area analyses, encompassing disease mapping, geographic correlation studies, disease clusters, and clustering. Advances in geographic information systems, statistical methodology, and availability of high-resolution, geographically referenced health and environmental quality data have created unprecedented new opportunities to investigate environmental and other factors in explaining local geographic variations in disease. They also present new challenges. Problems include the large random component that may predominate disease rates across small areas. Though this can be dealt with appropriately using Bayesian statistics to provide smooth estimates of disease risks, sensitivity to detect areas at high risk is limited when expected numbers of cases are small. Potential biases and confounding, particularly due to socioeconomic factors, and a detailed understanding of data quality are important. Data errors can result in large apparent disease excess in a locality. Disease cluster reports often arise nonsystematically because of media, physician, or public concern. One ready means of investigating such concerns is the replication of analyses in different areas based on routine data, as is done in the United Kingdom through the Small Area Health Statistics Unit (and increasingly in other European countries, e.g., through the European Health and Environment Information System collaboration). In the future, developments in exposure modeling and mapping, enhanced study designs, and new methods of surveillance of large health databases promise to improve our ability to understand the complex relationships of environment to health

New Insights into Amino Acid Preservation in the Early Oceans Using Modern Analytical Techniques

Protein- and non-protein-amino acids likely occupied the oceans at the time of the origin and evolution of life. Primordial soup-, hydrothermal vent-, and meteoritic-processes likely contributed to this early chemical inventory. Prebiotic synthesis and carbonaceous meteorite studies suggest that non-protein amino acids were likely more abundant than their protein-counterparts. Amino acid preservation before abiotic and biotic destruction is key to biomarker availability in paleoenvironments and remains an important uncertainty. To constrain primitive amino acid lifetimes, a 1992 archived seawater/beach sand mixture was spiked with D,L-alanine, D,L-valine (Val), alpha-aminoisobutyric acid (alpha-AIB), D,L-isovaline (Iva), and glycine (Gly). Analysis by high performance liquid chromatography with fluorescence detection (HPLC-FD) showed that only D-Val and non-protein amino acids were abundant after 2250 days. The mixture was re-analyzed in 2012 using HPLC-FD and a triple quadrupole mass spectrometer (QqQ-MS). The analytical results 20 years after the inception of the experiment were strikingly similar to those after 2250 days. To confirm that viable microorganisms were still present, the mixture was re-spiked with Gly in 2012. Aliquots were collected immediately after spiking, and at 5- and 9-month intervals thereafter. Final HPLC-FD/QqQ-MS analyses were performed in 2014. The 2014 analyses revealed that only alpha-AIB, D,L-Iva, and D-Val remained abundant. The disappearance of Gly indicated that microorganisms still lived in the mixture and were capable of consuming protein amino acids. These findings demonstrate that non-protein amino acids are minimally impacted by biological degradation and thus have very long lifetimes under these conditions. Primitive non-protein amino acids from terrestrial synthesis, or meteorite in-fall, likely experienced great-er preservation than protein amino acids in paleo-oceanic environments. Such robust molecules may have reached a steady state concentration dependent on ocean circulation through hydrothermal systems and synthetic input processes. We are presently trying to estimate this concentration

Enhanced Tearing by Electrical Stimulation of the Anterior Ethmoid Nerve

PURPOSE. Electrical neurostimulation enhances tear secretion, and can be applied to treatment of dry eye disease. Using a chronic implant, we evaluate the effects of stimulating the anterior ethmoid nerve on the aqueous, lipid, and protein content of secreted tears. METHODS. Neurostimulators were implanted beneath the nasal mucosa in 13 New Zealand white rabbits. Stimulations (2.3-2.8 mA pulses of 75-875 ls in duration repeated at 30-100 Hz for 3 minutes) were performed daily, for 3 weeks to measure changes in tear volume (Schirmer test), osmolarity (TearLab osmometer), lipid (Oil-Red-O staining), and protein (BCA assay, mass spectrometry). RESULTS. Stimulation of the anterior ethmoid nerve in the frequency range of 30 to 90 Hz increased tear volume by 92% to 133% (P 0.01). Modulating the treatment with 50% duty cycle (3 seconds of stimulation repeated every 6 seconds) increased tear secretion an additional 23% above continuous stimulation (P 0.01). Tear secretion returned to baseline levels within 7 minutes after stimulation ended. Tear film osmolarity decreased by 7 mOsmol/ L, tear lipid increased by 24% to 36% and protein concentration increased by 48% (P 0.05). Relative abundance of the lacrimal gland proteins remained the same, while several serum and corneal proteins decreased with stimulation (P 0.05). CONCLUSIONS. Electrical stimulation of the anterior ethmoid nerve increased aqueous tear volume, reduced tear osmolarity, added lipid, and increased the concentration of normal tear proteins. Human studies with an intranasal stimulator should verify these effects in patients with aqueous-and lipid-deficient forms of dry eye disease

Induction of Inflammation by West Nile virus Capsid through the Caspase-9 Apoptotic Pathway

West Nile virus (WNV) is a member of the Flaviviridae family of vector-borne pathogens. Clinical signs of WNV infection include neurologic symptoms, limb weakness, and encephalitis, which can result in paralysis or death. We report that the WNV-capsid (Cp) by itself induces rapid nuclear condensation and cell death in tissue culture. Apoptosis is induced through the mitochondrial pathway resulting in caspase-9 activation and downstream caspase-3 activation. Capsid gene delivery into the striatum of mouse brain or interskeletal muscle resulted in cell death and inflammation, likely through capsid-induced apoptosis in vivo. These studies demonstrate that the capsid protein of WNV may be responsible for aspects of viral pathogenesis through induction of the apoptotic cascade

Factors contributing to delays in diagnosis of breast cancers in Ghana, West Africa

BACKGROUND: Late diagnoses and poor prognoses of breast cancer are common throughout Africa. METHODS: To identify responsible factors, we utilized data from a population-based case-control study involving 1,184 women with breast malignancies conducted in three hospitals in Accra and Kumasi, Ghana. Interviews focused on potential breast cancer risk factors as well as factors that might contribute to presentation delays. We calculated odds ratios (OR) and 95% confidence intervals (CI) comparing malignances with biopsy masses larger than 5 cm. (62.4% of the 1,027 cases with measurable lesions) to smaller lesions. RESULTS: In multivariate analyses, strong predictors of larger masses were limited education (OR=1.96, 95% CI 1.32–2.90 <primary vs. ≥senior secondary school), being separated/divorced or widowed (1.75, 1.18–2.60 and 2.25, 1.43–3.55, respectively, vs. currently married), delay in care seeking after onset of symptoms (2.64, 1.77–3.95 for ≥12 vs. ≤2 months), care having initially been sought from someone other than a doctor/nurse (1.86, 0.85–4.09), and frequent use of herbal medications/treatment (1.51, 0.95–2.43 for ≥3x/day usage vs. none),. Particularly high risks associated with these factors were found among less educated women; for example, women with less than junior secondary schooling who delayed seeking care for breast symptoms for 6 months or longer were at nearly 4-times the risk of more educated women who promptly sought assistance. CONCLUSIONS: Our findings suggest that additional communication, particularly among less educated women, could promote earlier breast cancer diagnoses. Involvement of individuals other than medical practitioners, including traditional healers, may be helpful in this process

Associations of fecal microbial profiles with breast cancer and non-malignant breast disease in the Ghana Breast Health Study

The gut microbiota may play a role in breast cancer etiology by regulating hormonal, metabolic and immunologic pathways. We investigated associations of fecal bacteria with breast cancer and nonmalignant breast disease in a case-control study conducted in Ghana, a country with rising breast cancer incidence and mortality. To do this, we sequenced the V4 region of the 16S rRNA gene to characterize bacteria in fecal samples collected at the time of breast biopsy (N = 379 breast cancer cases, N = 102 nonmalignant breast disease cases, N = 414 population-based controls). We estimated associations of alpha diversity (observed amplicon sequence variants [ASVs], Shannon index, and Faith's phylogenetic diversity), beta diversity (Bray-Curtis and unweighted/weighted UniFrac distance), and the presence and relative abundance of select taxa with breast cancer and nonmalignant breast disease using multivariable unconditional polytomous logistic regression. All alpha diversity metrics were strongly, inversely associated with odds of breast cancer and for those in the highest relative to lowest tertile of observed ASVs, the odds ratio (95% confidence interval) was 0.21 (0.13-0.36; Ptrend &lt; .001). Alpha diversity associations were similar for nonmalignant breast disease and breast cancer grade/molecular subtype. All beta diversity distance matrices and multiple taxa with possible estrogen-conjugating and immune-related functions were strongly associated with breast cancer (all Ps &lt; .001). There were no statistically significant differences between breast cancer and nonmalignant breast disease cases in any microbiota metric. In conclusion, fecal bacterial characteristics were strongly and similarly associated with breast cancer and nonmalignant breast disease. Our findings provide novel insight into potential microbially-mediated mechanisms of breast disease